This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The thrust of progress during this period centered on understanding liver immune responses in patients with chronic HCV infection and characterizing the functional deficits of intrahepatic CD8+ T cells from these patients. Studying patients with chronic HCV infection, we find that liver infiltrating CD8+ T cells are highly activated, but they display profound deficits in proliferative capacity, cytokine production, and effector molecule production that was linked to high PD-1 expression and low IL-2 signaling. These cells also are susceptible to a cytokine withdrawal mediated apoptosis. In addition to this work, we have enrolled patients with spontaneous resolution of HCV infection in order to evaluate the phenotype, PD-1 expression and functionality of HCV specific CD8+ T cells from these patients.